My Section within the NIMH IRP, the Section on Affective Cognitive Neuroscience (SACN), focuses on three neuro-cognitive mechanisms that when dysfunctional places the individual at risk for Conduct Disorder (CD). These are: (i) an amygdala-centric system involved in responding to others' distress (fear, sadness, pain), which when compromised, is associated with increased CU traits (reduced guilt and empathy) and instrumental aggression; (ii) the basic threat systems implicating the amygdala, hypothalamus and periaqueductal gray (PAG) associated with, we hypothesize, increased risk for (threat-based) reactive aggression; and (iii) systems implicated in reinforcement-based decision-making (in particular, striatum and vmPFC), associated, when compromised, with impulsivity. Importantly, dysfunction in these mechanisms increases risk for specific symptom sets across psychiatric disorders. These mechanisms can be considered components of the RDoC negative, positive and social processes systems and are of critical relevance to the understanding of mood, anxiety and externalizing disorders. The work of the SACN takes the form of three sets of studies: (i) We conduct fMRI and behavioral studies with healthy adolescents and adults. These studies involve novel tasks designed to assess predictions regarding the functional properties of the neuro-cognitive systems briefly described above. In addition, they allow us to determine their development across adolescence and into early adulthood. (ii) We conduct fMRI and behavioral studies of youth with CD and comparison youth. These studies test whether the identified functional properties of the neural systems under investigation are dysfunctional in our target patient populations; (iii) We engage in collaborative studies. These studies involve intramural (e.g., David Goldman [NIAAA], Daniel Pine [NIMH] and Ellen Liebenluft [NIMH]) and extramural (e.g., Jeff Newcorn at Mt Sinai and Essi Viding at University College London) collaborations with national and international researchers, investigating both patients with elevated CU traits as well as other psychiatric conditions (e.g., mood and anxiety conditions). This work consumes very minimal amounts of SACN resources but provides an invaluable service: we gain a greater understanding of the functional properties of the neuro-cognitive systems relevant to CD by understanding how they can become perturbed in other clinical conditions. Proposed research: The current proposal builds upon and extends my previous research. In particular, the current proposal concentrates on understanding the basic threat systems (amygdala-hypothalamus-PAG) and vmPFC's representation of response value and the role of this in regulating behavior. The goals of this proposal are to determine: (i) the relative contribution of dysfunction in these systems to clinica irritability/reactive aggression in adolescents; and (ii) the extent that the positive relationship between past abuse/neglect and irritability/reactive aggression is mediated by dysfunction in the target systems. Given the large number of psychiatric conditions known to the associated with increased irritability, successful identification of irritability biomarkers will have widespread applicability for guiding treatment and identifying specific treatment targets for the individual patient. Moreover, since high levels of irritability in adolescence, the identification of such biomarkers will potentially allow us to identify individuals at risk for the development of mood and anxiety conditions. We will recruit 360 adolescents (half male, half 10-13 years in age, half 14-17 years in age, 120 patients and 60 healthy comparison youth within each age range). Each participant will experience four paradigms across two fMRI sessions. Three tasks assess the responsiveness of the candidate neuro-cognitive mechanisms to three known triggers of this circuitry (i.e., perceived looming threats, frustrative non-reward and social provocation). This wil allow us to determine the extent to which the relationship between neural dysfunction and irritability/ reactive aggression is trigger specific. The fourth task (passive avoidance learning)is designed to assess vmPFC's role in the representation of response value in a context not involving basic threat system regulation. In addition, they will receive a full assessment of their psychiatric symptomatology. Our principle analysis will be based on 10 fMRI ROI biomarker parameters identified through test-retest (ICC) analyses; i.e., our fMRI biomarkers are reliable indices of the functional processes investigated. Based on our preliminary findings, we hypothesize that increased responses within the amygdala-hypothalamus-PAG to looming treats, frustrative non-reward and social provocation and corresponding decreased regulatory activity by vmPFC will be positively associated with increased levels of irritability/reactive aggression. In addition, we hypothesize that dysfunction in the target systems will mediate the positive relationship of past abuse/neglect and irritability/reactive aggression.